PROJECT SUMMARY/ ABSTRACT This proposal addresses the compelling public health issue of the problem of childhood obesity in the Hispanic (Mexican-American) population. In this context, one of the most striking epidemiological observations is that Hispanic immigrants in the U.S. exhibit a progressive and pronounced decline in health (obesity/ adiposity) over time and across generations that is evident even after accounting for socioeconomic status. The prevailing paradigm invokes the construct of acculturation (post-migration acquisition of host culture and/or loss of heritage culture) and posits this health decline is a biological consequence of some of acculturation?s psychosocial and behavioral sequelae (increasing stress, declining social ties, adoption of unhealthy diet). However, research has overlooked one crucial point: a major feature of this phenomenon is its intergenerational component, and yet intergenerational transmission is unaddressed. Our proposal seeks to address this important limitation. We propose that the cause of the observed intergenerational escalation in obesity among Mexican-Americans may, in part, originate during the intrauterine period of life. At this time, maternal acculturation-related processes may impact fetal development to produce phenotypic alterations in the structure and function of cells, tissues and organ systems that increase susceptibility for obesity/adiposity (i.e., the concept of ?fetal/developmental programming of health and disease risk?). We propose to conduct a prospective, longitudinal study in a representative cohort of N=300 first- and second- generation Mexican-American mothers and their offspring from early gestation through birth till 6-month age. We will conceptualize, operationalize and analyze acculturation as a multi-dimensional construct. We will quantify child adiposity (% fat mass) at birth and at 6-mo age by dual-energy X-ray absorptiometry (DXA) whole-body imaging. We will address the following specific aims: Aim 1: Test the hypothesis that maternal acculturation is prospectively associated with newborn and infant body composition (adiposity). Aim 2: Test the hypothesis that gestational endocrine (cortisol, CRH), immune (IL-6, TNF-?, CRP), oxidative (5-iPF2?-VI), and metabolic (glucose, insulin) biology across pregnancy mediates the effect of maternal acculturation on newborn and infant body composition (adiposity). Aim 3: Identify and quantify the potentially modifiable maternal psychological, behavioral and biophysical characteristics that are associated with acculturation and may account for its impact on gestational biology and child body composition (adiposity). We have assembled an interdisciplinary team of established investigators with complementary expertise; performed a feasibility analysis documenting our ability to recruit and retain the proposed study population and implement all elements of the study protocol; and collected and present preliminary data in support of the key tenets of our proposal. Our study will generate new information about the health of Mexican Americans, shed more light on the causes and mechanisms of intergenerational cycles of vulnerability, and provide a basis for developing specific translational targets for future intervention studies.